Structural Biology of TGF-β signalling

Activins, Bone Morphogenetic Proteins (BMPs) and Growth and Differentiation Factors (GDFs) are members of the TGF-β family of growth factors. They play a vital role in the early embryonic development in vertebrates and are essential for homeostasis of adult organisms. These dimeric, disulfide rich proteins are essential for essential for many biological processes that happen in our body and their misregulation is implicated in many diseases, cancer in particular.

These growth factors signal through two the type I and type II receptors, which both contain a single snake-toxin related domain in their extracellular part. A single dimeric growth factor binds two of each receptors forming a 1:2:2 complex.

There are also several protein inhibitors that can inactivate these growth factors by binding them and preventing interactions with receptors. These inhibitors include follistatin, gremlin, noggin and chordin, among others.

We are studying the activins, GDFs and BMPs and their interacting proteins using biochemical and biophysical methods and try to solve crystal structures of various complexes. We have particular interest in inhibition of activins by follistatin and on the regulation of the growth factors by their pro-domains. We aim to understand the mechanism by which the signalling is transduce and how it is regulated in the extracellular space, and to define the determinants of specificity of different interactions.